Dual mechanism inhibitors for the treatment of disease
AssigneeAerie Pharmaceuticals, Inc.
InventorsMitchell A. deLong, Jill Marie Sturdivant, Susan M. Royalty
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Abstract
Provided are compounds that are inhibitors of both rho kinase and of a monoamine transporter (MAT) act to improve the disease state or condition. Further provided are compositions comprising the compounds. Further provided are methods for treating diseases or conditions, the methods comprising administering compounds according to the invention. One such disease may be glaucoma for which, among other beneficial effects, a marked reduction in intraocular pressure (IOP) may be achieved.
Claims33
A compound according to Formula I:
- and salts thereof,
- wherein R1, R2, and R3 are independently hydrogen, C1-C4 alkyl, aryl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, C1-C4 carboxyl, or form a ring with each other or with A;
- wherein A is C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, or forms a ring structure with R1, R2 or R3;
- wherein B is hydrogen, an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C22 alkyl, C1-C22 alkyl aryl, C1-C22 alkyl heteroaryl, C2-C22 alkenyl, C2-C22 alkynyl, C1-C22 carbonyl, C1-C22 carbonylamino, C1-C22 alkoxy, C1-C22 sulfonyl, C1-C22 sulfonylamino, C1-C22 thioalkyl, or C1-C22 carboxyl;
- wherein X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl;
- wherein the double circle
- indicates an aromatic or heteroaromatic ring;
- and
- wherein each Z is independently a bond, is C1-C4 alkyl, heteroalkyl, or an O atom.
A compound according to Formula III:
- and salts and solvates thereof,
- wherein R1 and R2 are independently hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, or R1 and R2 together form a ring, either cycloalkyl or heterocycloalkyl;
- wherein R3 is hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl, or R3 may from a ring with itself or R1 or R2;
- wherein X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl;
- wherein B is hydrogen, C1-C18 alkyl, C1-C18 alkyl aryl, C1-C18 alkyl heteroaryl, C1-C18 carbonyl, C1-C18 carbonylamino, C1-C18 sulfonyl, C1-C18 sulfonylamino, or C1-C18 carboxyl;
- and
- wherein each Z is independently a bond, is C1-C4 alkyl, heteroalkyl, or an O atom.
A compound according to Formula IV:
- and salts thereof,
- wherein R1 and R2 are independently hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C1-C4 alkyl heterocyclyl, or R1 and R2 together form a ring, either cycloalkyl or heterocyclyl;
- wherein R3 is a hydrogen, C1-C4 alkyl, C1-C4 alkyl aryl, C1-C4 alkyl heteroaryl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl;
- wherein X1, X2, and X3 are, independently, hydrogen, hydroxyl, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, amino, aminocarbonyl, nitro, cyano, C1-C4 carbonyl, C1-C4 carbonylamino, C1-C4 alkoxy, C1-C4 sulfonyl, C1-C4 sulfonylamino, C1-C4 thioalkyl, or C1-C4 carboxyl;
- wherein B is hydrogen, C1-C18 alkyl, C1-C18 alkyl aryl, C1-C18 alkyl heteroaryl, C1-C18 carbonyl, C1-C18 carbonylamino, C1-C18 sulfonyl, C1-C18 sulfonylamino, or C1-C18 carboxyl;
- and
- wherein Z is a bond, C1-C4 alkyl, heteroalkyl, or an O atom.
A compound according to Formula V:
- wherein Z is a bond or —CH2—;
- and
- B is an aryl group, a heteroaryl group, a cycloalkyl group, a heterocycloalkyl group, C1-C22 alkyl, C1-C22 alkyl aryl, C1-C22 alkyl heteroaryl, C2-C22 alkenyl, C2-C22 alkynyl, C1-C22 carbonyl, C1-C22 carbonylamino, C1-C22 alkoxy, C1-C22 sulfonyl, C1-C22 sulfonylamino, C1-C22 thioalkyl, or C1-C22 carboxyl.
A compound selected from the group consisting of:
A compound according to Formula (VI):
- wherein R4 is methyl and n is 2.
4-(3-Amino-1-(isoquinolino-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate.
Dependencies are inferred from the claim text.